SUMMARY One of the main goals of aging research is to discover interventions that can prolong lifespan and healthspan, the healthy years of life. In the current proposal we focus on a novel treatment toward this end: the restriction of phosphate and potassium in the diet. Against a backdrop of landmark studies of lifespan extension under restriction of carbon and sulfur, the role of dietary phosphate and potassium has been almost completely passed over by the aging research community. In preliminary experiments using yeast as a model system, we have seen that phosphate and potassium restriction extends lifespan up to 24% relative to standard conditions. This effect is a particularly compelling target for aging research focused on human health, since any clinical applications could make use of currently available drug mimetics of phosphate and potassium starvation. To enable any such translational undertaking, however, we must know enough about the longevity evoked by these regimens to design effective treatments. We propose to use invertebrate model systems for a series of rapid, relatively cheap, and conclusive experiments to establish which phosphate and potassium binder drugs extend lifespan and how. In Aim 1 we screen these drugs in yeast using a rigorous microfluidic system for lifespan assays, and we investigate the mechanisms by which genetic and environmental micronutrient starvations exert their effects. In Aim 2 we screen the most compelling drugs for effects on lifespan and healthspan in nematode worms. Together, these experiments will serve as a springboard for the testing of pro- lifespan, pro-healthspan treatments and genes in mammalian systems.